Role of the intestinal immune system in autoimmune diseases

Research in recent years has indicated a complex relationship between the intestinal immune system, the intestinal microbiota and the integrity of the intestinal barrier in the development of autoimmune diseases.

The interaction of the human organism with the intestinal microbiota (all microorganisms in the intestines) is crucial both for the development of the intestinal immune system and for maintaining the homeostasis of the intestine and the whole organism.

The modern way of life and the changed environmental conditions disturb the balance between the intestinal immune system and the microbiota, which coincides with the large increase in autoimmune, allergic and chronic inflammatory diseases in recent years.

Although there is evidence that the composition of the intestinal microbiota and increased permeability of the intestinal barrier are associated with various autoimmune diseases, the mechanisms by which the gut microbiota can affect the initiation of autoimmunity to distant tissues and organs have not been fully elucidated.

Recent studies are also examining ways to modulate the intestinal immune system, gut microbiota and intestinal barrier permeability as new therapeutic approaches for the prevention and treatment of autoimmune diseases.

1. What makes the intestinal immune system

The intestinal immune system consists of gut-associated lymphoid tissue (GALT) as part of the lymphoid tissue of the mucous membranes in various human organs (mucosa-associated lymphoid tissue-MALT). The lymphoid tissue of the intestine consists of Peyer’s patches, lymphoid tissue in the crypts of the intestine, isolated lymphoid follicles (ILF), appendix and mesenteric lymph nodes, as well as diffusely distributed immune cells in the loose connective tissue of the intestinal mucosa (lamina propria).

The cells that make up the lymphoid tissue of the intestine are M cells, which can transmit antigens but not process them or present them to immune cells, helper T lymphocytes (Th), regulatory T lymphocytes (Tregs), cytotoxic T cells (Tc), B lymphocytes producing IgA, phagocytes including dendritic cells and macrophages, as antigen presenting cells. Recently discovered innate lymphoid cells (ILC) have a particularly important role in maintenance of homeostasis in the intestinal immune system.

2. What is the role of the intestinal immune system

The intestinal mucosa covers the largest area of ​​the body and is constantly exposed to a huge number of different microbes, mostly bacteria, food antigens and toxins. The intestinal immune system has the ability to distinguish harmful, pathogenic from commensal, non-pathogenic microbes, as well as food antigens. Immune cells of the intestinal mucosa “tolerate” commensal microbes, i.e. they do not trigger an immune response towards them.

The immune system in the gut has a dual function:

  • It is the main line of defense in the intestines – innate immunity cells (mainly myeloid cells) non-specifically recognize pathogenic microbes, present their antigens and thus activating the cells of the adaptive immune system (lymphocytes).
  • It  maintains immune tolerance to harmless, commensal  intestinal microbes and food antigens.

The dual function of the intestinal immune system is crucial in maintaining the homeostasis of the intestine and the whole organism.

3. What is the intestinal microbiota

The microbiota is a unique micro-ecosystem created by the co-evolution of bacteria and other microorganisms (fungi, protozoa, etc.) with its multicellular hosts, including the human body. The human body is not a closed system, nor is it sterile, and microorganisms inhabit the skin, gastrointestinal tract, respiratory organs and urogenital tract. In these organ systems, a local microbiota develops with characteristic properties and the content of microorganisms, so that the microbiota is unique for each person. In general, the microbiota shares a survival niche with its hosts and has unique and crucial roles in physiological and pathological processes.

The gastrointestinal tract has the largest area of ​​mucosa compared to other organ systems inhabited by microbiota. Accordingly, the largest community of microorganisms with the greatest diversity resides in the intestines, and it is estimated to consist of over 500 different species. The total number of microbes reaches 1014-1015, which is up to 100 times more than the number of cells in the human body.

The gut microbiota has several unique roles:

  • helps in the process of digestion
  • synthesizes nutrients, metabolites important for the function of intestinal immune cells
  • regulates the defense and tolerogenic functions of the immune cells in the gut
  • enables the development of the intestinal immune system

In relation to the intestinal immune system, the microbiota has a dual function:

  • gut microbiota is necessary for the structural development of the lymphoid tissue of the intestine (GALT) during the development of the organism
  • gut microbiota affects the function of intestinal immune cells in the adult organism

4. What makes the intestinal barrier

The intestinal barrier is a dynamic and semipermeable barrier that allows the absorption of nutrients, electrolytes and water, as well as antigens that play a role in immunoregulation, but also protects the host from microbes as well as potentially toxic molecules in the intestinal lumen.

The intestinal barrier consists of three interconnected layers: mucus, intestinal epithelium and the immune system in the intestinal mucosa.

Intestinal mucus is composed of complex glycoproteins and forms the first line of the intestinal barrier. Mucus has antimicrobial activity because it contains antimicrobial peptides (AMP) and secretory IgA, which is the most abundant immunoglobulin on the surface of the intestinal mucosa that binds bacteria in the intestinal lumen or neutralizes bacterial toxins.

Intestinal epithelium forms the most important physical barrier on the surface of the intestinal mucosa and is composed of several types of cells with certain functions. Intestinal epithelial cells are interconnected through structures called “tight junctions” (TJs). Substances from the intestinal lumen can cross this barrier through two general pathways, transcellular or paracellular.

Immune cells of the intestinal mucosa are located below the intestinal epithelium in the lamina propria, but they also exist in the epithelium itself. The intestinal mucosa is the largest organ of the immune system in the human body.

The interaction between all three components of the intestinal mucosal barrier is complex, but is well regulated to maintain intestinal homeostasis.

The complexity of the intestinal barrier function is reflected in the ability of the intestine to perform two opposite functions:

  • gut barrier ensures the selective permeability of the required nutrients from the intestinal lumen into the circulation and into the internal milieu
  • gut barrier prevents the penetration of harmful factors, including microorganisms, certain food antigens as potentially toxic or pro-inflammatory factors.

Collectively, three main “barriers” prevent the penetration of harmful microbes and antigens from the intestinal lumen into the body:

  1. Biological barrier formed by the intestinal microbiota, responsible for resistance to colonization by pathogenic microbes and which affects the function of immune cells.
  2. Mechanical barrier consisting of mucus and intestinal epithelial cells. Epithelial cells come into the closest possible contact in the most apical part through structures called “tight junctions” (TJs) that bind cells together and restrict the passage of ions, molecules and cells through the paracellular space.
  3. Immune barrier consisting of intestinal lymphoid tissue (GALT) with effector and regulatory T cells, IgA-producing B cells and plasmacytes, innate lymphoid cells and resident macrophages and dendritic cells.

5. Autoimmunity and autoimmune diseases

Autoimmunity is characterized by the initiation of an immune response to self antigens, cells and tissues that is mediated by autoreactive T and B cells that have “escaped” the mechanisms of immune tolerance and that cause tissue damage mediated by antibodies or immune cells.

Autoimmunity can be classified as an organ specific or systemic based on the site of the autoimmune reaction and clinical manifestations. For example, rheumatoid arthritis, Sjögren’s syndrome, and systemic lupus erythematosus are examples of systemic autoimmune diseases, while type 1 diabetes, multiple sclerosis, and autoimmune hepatitis are examples of organ-specific autoimmune diseases.

6. What is the role of the intestinal immune system in autoimmune diseases

Genetic and epigenetic factors, as well as environmental factors, contribute to disruption of immune tolerance to self tissue antigens, and the development of autoimmune diseases in genetically predisposed individuals.

Patients with autoimmune diseases may also have a disturbed immune response to the intestinal microbiota, which causes a change in the content of microbes in the intestines and disturbed local homeostasis, a condition called dysbiosis. Dysbiosis and altered function of intestinal immune cells can contribute to the development of autoimmune intestinal diseases, but also other systemic or organ-specific autoimmune diseases.

Environmental factors that can change the intestinal microbiota and contribute to the development of dysbiosis are the use of drugs, especially antibiotics, diet, UV radiation, smoking, and hygienic conditions.

It is important to emphasize that the altered intestinal microbiota (dysbiosis) promotes dysregulation of the immune response in autoimmunity through several proposed mechanisms:

  • by promoting the differentiation of proinflammatory helper T lymphocytes Th1 and Th17 cells (T helper cell skewing)
  • by activation of autoreactive T and B lymphocytes independently of the antigen in the inflammatory milieu (bystander activation)
  • by epitope spreading
  • by cross-reactivity known as molecular mimicry with antigens microbe (cross-reactivity)
  • by stimulating the dual T cell receptor (TCR), a T cell receptor that recognizes both microbial antigens and antigens of own tissues (dual T cell receptor)

Loss of immune regulatory mechanisms, dysfunction and increased permeability of the intestinal barrier or certain inborn defects in the immune system contribute to the pathogenesis of intestinal diseases mediated by immune mechanisms. Disruption of host-microbiota homeostasis increases the likelihood of a strong immune response to the intestinal microbiota and the development of inflammatory bowel disease (IBD). Similarly, an altered immune response to food components promotes celiac disease.

However, an innate and adaptive immune response to the gut microbiota may also exist in organs outside the gut. Organs that are anatomically connected to the intestines (especially the pancreas and liver) are most exposed to the direct influence of the intestinal microbiota and its metabolites, which can contribute to the development of type 1 diabetes and autoimmune hepatitis.

Systemic effects of the altered intestinal microbiota also exist in the central nervous system (CNS) and can influence the development of multiple sclerosis. The effects in the gut-CNS axis are mediated by microbial metabolites, neurotransmitters, and immune cells and their mediators.

immune system

Brucklacher-Waldert V, Carr EJ, Linterman MA, Veldhoen M. Cellular Plasticity of CD4+ T Cells in the Intestine. Front Immunol. 2014 Oct 7;5:488. doi: 10.3389/fimmu.2014.00488.

7. Future research on the intestinal immune system in autoimmune diseases

Hippocrates’ quote “all diseases begin in the intestines” seems to be correct, over 2000 years later, for various pathological conditions. The role of the intestinal immune system, intestinal microbiota and intestinal barrier in health and disease is a scientific field of intensive research. Future research using genomics, transcriptomics, and proteomics may lead to specific and potentially personalized goals for therapeutic interventions in modulating intestinal immune cell function and controlling increased intestinal barrier permeability in autoimmune diseases.

In the Department of Immunology at the Institute for Biological Research “Siniša Stanković” in Belgrade, we conduct research in this area, to investigate the role of the intestinal immune system and microbiota in type 1 diabetes and multiple sclerosis using experimental models of these diseases.

Literature

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  2. Jiao Y, Wu L, Huntington ND, Zhang X. Crosstalk Between Gut Microbiota and Innate Immunity and Its Implication in Autoimmune Diseases. Front Immunol. 2020 Feb 21;11:282. doi: 10.3389/fimmu.2020.00282. PMID: 32153586; PMCID: PMC7047319.
  3. Marietta E, Horwath I, Balakrishnan B, Taneja V. Role of the intestinal microbiome in autoimmune diseases and its use in treatments. Cell Immunol. 2019 May;339:50-58. doi: 10.1016/j.cellimm.2018.10.005. Epub 2018 Oct 19. PMID: 30366573.
  4. Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol. 2017 Sep;11(9):821-834. doi: 10.1080/17474124.2017.1343143. Epub 2017 Jun 26. PMID: 28650209; PMCID: PMC6104804.
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